All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Treatments using nucleic acid-based drugs such as DNA, antisense oligonucleonucleotides, small interfering RNA (siRNA), micro-RNA and/or aptamers are attractive but sometimes challenging. For example, nucleic acid-based drugs that specifically target oncogenes have the potential to block the unique initiation and propagation pathways of cancer cells, but their clinical application can be hindered due to the lack of safe and efficient drug delivery systems. Besides being non-toxic and non-immunogenic, an ideal drug delivery system for nucleic acid-based therapeutics must be able to assist the escape of therapeutics from the endosome so that the nucleic acid-based drug can be released into the cytoplasm where it can function.
Previously, it was believed that direct cytoplasmic delivery may be achievable using cell penetrating peptides (CPPs) which translocate across the cell membrane, thus bypassing the barrier of endosome and directly delivering their cargo into the cytoplasm (Elliott, G.; Cell 1997, 88, (2), 223-33). However, additional studies revealed that the internalization of most CPPs actually involve endocytosis (Trehin, R.; Eur J Pharm Biopharm 2004, 58, (2), 209-23). Moreover, most biomolecules are internalized by cells through endocytosis and are subsequently channeled into endosomal-lysosomal compartments, resulting in total loss of activity in lysosome if they do not possess the machinery to escape from the endosome. Thus, the endosome is a major barrier for cytoplasmic delivery of nucleic acid-based therapeutics and drug delivery systems must be designed to destabilize the endosome membrane to assist the escape of the therapeutics.
Thus, there is a need in the art for an effective cytoplasmic drug delivery system that can destabilize the endosome membrane.